EP3038617A1 - Method for treating amyotrophic lateral sclerosis by inhibition of cxcr4/cxcl12 signaling - Google Patents
Method for treating amyotrophic lateral sclerosis by inhibition of cxcr4/cxcl12 signalingInfo
- Publication number
- EP3038617A1 EP3038617A1 EP14776926.9A EP14776926A EP3038617A1 EP 3038617 A1 EP3038617 A1 EP 3038617A1 EP 14776926 A EP14776926 A EP 14776926A EP 3038617 A1 EP3038617 A1 EP 3038617A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- cxcr4
- amd3100
- als
- mice
- inhibitor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Definitions
- This invention generally relates to the fields of amyotrophic lateral sclerosis (ALS) pathology and CXCR4/CXCL12 signaling .
- ALS amyotrophic lateral sclerosis
- ALS Amyotrophic lateral sclerosis
- MN motor neuron
- B-CNS-B blood-central nervous system barrier
- Astrocytic cells are considered to have a primary role in the pathological process of amyotrophic lateral sclerosis (ALS), and are substantial contributers to motor neuron death.
- Astroglial abnormalities such as changes in the release and uptake of astrocytic glutamate preface clinical symptoms of the disease (Vargas et al . , 2010).
- Chemokines and their receptors in the central nervous system are relevant for the understanding of brain
- Chemokines are known to be plurifunctional and active on many different cell types, including neurons and glial cells.
- Chemokine receptors including the G-protein-coupled receptor CXCR4, are expressed widely in neurons and glial cell.
- the ligand of CXCR4 the chemokine stromal-derived factor 1 (SDF- 1), also known as CXCL12, evokes glutamate release and thereby modulates neuronal function or apoptosis.
- SDF-1 chemokine stromal-derived factor 1
- the mechanism of action starts with binding of CXCL12 to CXCR4, increase in [Ca2+] , stimulation of extracellular signal related kinases and release of TNFa from astrocyte and microglia cell surface (Allen et al . , 2001) .
- AMD3100 ( 1 , 1 '-[ 1 , 4-Phenylenebis (methylene) ] bis- 1 , 4 , 8 , 11-tetraazacyclotetradecane) is a bicyclam molecule that specifically and reversibly blocks SDF-1 binding to CXCR4.
- AMD3100 has been shown to rapidly mobilize hematopoietic stem and progenitor cells (HSPCs) from the bone marrow (BM) into the blood of mice, non-human primates and humans. Disruption of CXCR4 signaling by AMD3100 was seen to inhibit the migration activity of grafted neuronal stem/progenitor cells, as observed in hemiplegic mice (Arimitsu et al . , 2012). In 2008, AMD3100 was FDA-approved for HSPC mobilization in combination with
- G-CSF granulocyte colony stimulating factor
- AMD3100 has a regulatory role in the recruitment of pro-angiogenic cells and in the extent of revascularization (Petit et al . , 2007), which is extremely important in maintenance and function of central nervous system (CNS) neurons.
- CNS central nervous system
- B-CNS-B blood-Central Nervous System barrier
- BBB blood brain barrier
- BSCB blood-spinal cord barrier
- BCSFB blood-cerebrospinal fluid barrier
- MCP1 monocyte chemoattractant protein-1
- TNF- oi TNF- oi
- IL- ⁇ IFN- ⁇
- hemoglobin-derived products reductions in microcirculation and hypoperfusion.
- SOD1 mutants are proposed to mediate endothelial damage even before motor neuron death and hypoxia and
- the present invention provides a method for treating amyotrophic lateral sclerosis (ALS) which involves administering to a patient suffering from ALS an effective amount of an inhibitor of G protein-coupled receptor CXCR4.
- ALS amyotrophic lateral sclerosis
- the present invention further provides for the use of an inhibitor of G protein-coupled receptor CXCR4 for treating amyotrophic lateral sclerosis (ALS)
- an inhibitor of G protein-coupled receptor CXCR4 for treating amyotrophic lateral sclerosis (ALS)
- the present invention further provides for the use of an inhibitor of G protein-coupled receptor CXCR4 for treating amyotrophic lateral sclerosis (ALS)
- an inhibitor of G protein-coupled receptor CXCR4 for treating amyotrophic lateral sclerosis (ALS)
- the present invention further provides for the use of an inhibitor of G protein-coupled receptor CXCR4 for treating amyotrophic lateral sclerosis (ALS)
- G protein-coupled receptor CXCR4 for inhibiting glutamate release in astrocytes or for increasing remyelinization in motor neurons .
- Figure 1 is a Western blot analysis of CXCR4 and tubulin in transgenic G93A mice and non-transgenic litter mates (LM) at 30, 80 and 100 days old and at the final stage of the disease .
- Figure 2 is a graph showing CXCR4 levels in transgenic G93A mice and non-transgenic litter mates throughout disease progression (30, 80 and 100 days old and at the final stage) as a ratio of CXCR4 to actin.
- Figures 3A-3B are graphs showing survival (Fig. 3A) , weight change (Fig. 3B) , and performance on the Rotarod test (Fig. 3C) for G93A female mice subcutaneously treated with either AMD3100 or PBS, starting at 70 days old. Six mice received
- AMD3100 once a week eight mice received AMD3100 twice a week, and seven mice received PBS once a week.
- Figures 5A-5B show the effect of AMD3100 treatment on body weight and motor function of female SOD1-G93A mice.
- Figure 5B shows motor function of the female mice which was assessed by performing Rotorod test. The animals were trained to run on the 2-cm-diameter rod, which rotated at accelerating speed from 10 turns per minute to 40 turns per minute. The mice were allowed to run for up to 5 min in each trial, or until they fell off.
- Figure 6 shows increase in survival of NSC-34 cells stably transfected with mutant SOD1 which incubated with primary astrocytes treated with AMD3100.
- Primary astrocytes from 3 days old newborn SODG93A mice were incubated AMD3100 for 24h.
- Media of treated astrocytes was then added to NSC-34 cells stably
- Figures 7A-7B show inflammation levels displayed by activated microglia levels, following AMD3100 treatment. 50 days old female SODG93A mice were s.c injected with 5mg/kg AMD3100 twice a week. On 110 days old mice were sacrificed and analyzed using western blot for inflammatory markers of activated
- Fig 7A. is cd36 levels.
- Fig 7B. is Iba-1 levels.
- Figures 8A-8B show inflammatory cytokines levels following AMD3100 treatment. 50 days old female SODG93A mice were s.c injected with 5mg/kg AMD3100 twice a week. On 110 days old mice were sacrificed and analyzed for inflammatory cytokines.
- Fig 8A IL-6 levels using western blot analysis.
- Fig 8B TNF-a levels using ELISA.
- Figures 9A-9C show Blood-CNS-Barrier markers levels following AMD3100 treatment. 50 days old female SODG93A mice were s.c injected with 5mg/kg AMD3100 twice a week. On 110 days old mice were sacrificed and analyzed for B-CNS-B markers using western blot. Fig. 9A shows ZO-1 levels. Fig. 9B shows claudin 5 levels. Fig. 9C shows Occludin levels.
- FIG. 10 shows myelin levels, which is a dielectric material which forms a layer around neuronal axons, essential for increasing the speed at which impulses propagate along the axons and known to be depleted in ALS, following AMD3100 treatment. 50 days old female SODG93A mice were s.c injected with 5mg/kg
- AMD3100 twice a week On 110 days old mice were sacrificed and analyzed for myelin levels using western blot. Myelin levels were significantly increased following AMD3100 treatment.
- FIG 11 shows EAAT2 levels, which is the main
- AMD3100 twice a week On 110 days old mice were sacrificed and analyzed for EAAT2 levels using western blot. EAAT2 levels were increased following AMD3100 treatment.
- the present invention thus provides a method for treating amyotrophic lateral sclerosis (ALS) and involves administering to a patient suffering from ALS an effective amount of an antagonist/inhibitor of G protein-coupled receptor CXCR4 (use thereof in treating ALS) .
- the present invention is also directed to use of the antagonist/inhibitor in inhibiting
- the present invention is further directed to the antagonist/inhibitor in increasing remyelinization in motor neurons. Accordingly, also provided by the present
- inventions are a method for inhibiting glutamate release in astrocytes and a method for increasing remyelinization in motor neurons .
- treating with respect to amyotrophic lateral sclerosis is intended to mean substantially inhibiting, slowing or reversing the progression of amyotrophic lateral sclerosis, such as reducing or inhibiting motor neuron (MN) death, or substantially ameliorating one or more clinical symptoms of amyotrophic lateral sclerosis, such as diminished motor function.
- MN motor neuron
- the antagonist/inhibitor of CXCR4 is preferably the bicyclam, 1 , 1 ' - [ 1 , 4-Phenylenebis (methylene) ] is-1 , 4, 8, 11- tetraazacyclotetradecane (also known as AMD3100 or Plerixafor) or a pharmaceutically acceptable salt thereof.
- Antagonists/ inhibitors of CXCR4 are well known in the art, and non-limiting examples of such antagonists/inhibitors of CXCR4 include other bicyclams AMD3196, AMD3207, AMD3203, AMD3109, AMD3128, AMD3166, AMD2763, AMD3070, AMD3209, AMD3068, AMD3208, AMD3120, AMD6037, AMD3390, and AMD6038 (Este et al., 1999).
- Transition metal ions preferably Cu2+, Zn2+, or Ni2+, may be incorporated into the cyclam rings of the above compounds (Gerlach et al . , 2003) .
- Further non-limiting examples of antagonists/inhibitors of CXCR4 for use in the present invention include the CXCR4 peptide antagonist CTCE-9908 (amino acid sequence KGVSLSYR-X- RYSLSVGK; Faber et al .
- a "pharmaceutical composition” refers to a pyrogen-free preparation of an effective amount of a CXCR4 antagonist/inhibitor, as the active ingredient, with other chemical components such as physiologically suitable carriers and excipients.
- the purpose of a pharmaceutical composition is to facilitate administration of a compound to a patient.
- excipient refers to an inert substance added to a pharmaceutical composition to further facilitate
- Non-limiting examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
- oral including buccal or sublingual
- rectal nasal, topical
- Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the
- Suitable routes of administration may, for example, include transnasal or parenteral delivery, including
- intramuscular, subcutaneous and intramedullary injections as well as administration directly to the brain, e.g., intracranial administration, as well as injection or infusion into the cerebrospinal fluid.
- intracranial administration as well as injection or infusion into the cerebrospinal fluid.
- administration is by intrathecal injection or infusion
- intraventricular injection or infusion intraparenchymal
- administration is by intraparenchymal injection; intracerebroventricular injection; or intracerebroventricular infusion .
- Methods for achieving the delivery of the active ingredient and a pharmaceutical composition containing the active ingredient are well known to those skilled in the art of drug delivery. Specific examples include delivery intrathecally by mini-osmotic pump (Ignacio et al., 2005); delivery directly into muscle (s) by syringe or mini osmotic pump (Azzouz et al., 2005); directly administered to peritoneum by syringe or mini osmotic pump (Kieran et al., 2004); delivery directly below the skin by syringe (Reinholz et al., 1999); and delivery directly to the ventricles in the brain by injection or using a small catheter attached to an osmotic pump (Sathasivam et al . , 2005) .
- An implant e.g., small silicon implant
- compositions for use in accordance with the present invention may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active ingredients into preparations which can be used
- administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or
- the active ingredient component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
- an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
- Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol . Flavoring, preservative, dispersing, and coloring agent can also be present.
- Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths.
- Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol can be added to the powder mixture before the filling operation.
- a disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
- suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture.
- suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose,
- Lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like.
- Disintegrators include, without limitation, starch, methyl cellulose, agar, betonite, xanthan gum, and the like. Tablets are formulated, for example, by preparing a powder mixture,
- a powder mixture is prepared by mixing the compound, suitable comminuted, with a diluent or base as
- the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen.
- a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen.
- the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
- the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil.
- lubricated mixture is then compressed into tablets.
- the compounds of the present disclosure can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
- a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material, and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.
- Oral fluids such as solution, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
- Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic vehicle.
- Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,
- flavor additive such as peppermint oil or natural sweeteners, or saccharin or other artificial sweeteners, and the like can also be added.
- dosage unit formulations for oral administration can be microencapsulated.
- the formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax, or the like.
- the active ingredient, and pharmaceutically acceptable salts thereof, can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
- liposomes can be formed from a variety of phopholipids , such as cholesterol, stearylamine , or phophatidylcholines .
- compositions of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee- making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
- the active ingredient may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological salt buffer.
- physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological salt buffer.
- penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
- the active ingredients for use according to the present invention are conveniently delivered in the form of an aerosol spray
- a suitable propellant e.g., dichlorodifluoromethane
- a nasal spray which does not require a pressurized pack or nebulizer as in an inhalation spray, can alternatively used for intranasal administration.
- the dosage unit may be determined by providing a valve to deliver a metered amount.
- Capsules and cartridges of, e.g., gelatin for use in a dispenser may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
- compositions described herein may be formulated for parenteral administration or administration directly to the brain, e.g., by bolus injection or continuous infusion.
- Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multidose containers with optionally, an added preservative.
- the compositions may be suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
- administration or administration directly to the brain include aqueous solutions of the active preparation in water-soluble form. Additionally, suspensions of the active ingredients may be prepared as appropriate oily or water based injection
- Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate, triglycerides or liposomes.
- Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran.
- the suspension may also contain suitable stabilizers or agents which increase the solubility of the active ingredients to allow for the preparation of highly concentrated solutions.
- the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water based solution, before use.
- a suitable vehicle e.g., sterile, pyrogen-free water based solution
- compositions suitable for use in the context of the method of the present invention include
- compositions wherein the active ingredient is contained in an amount effective to achieve the intended purpose. More
- an effective amount means an amount of active ingredient ( s ) effective to treat ALS, such as, for example, an amount which results in a clinically significant reduction or prevention of neuronal injury or death, or axonal degeneration.
- Dosage amount and interval may be adjusted individually to levels of the active ingredient (CXCR4 antagonist/inhibitor) which are sufficient to treat the particular neurodegenerative tauopathy (minimal effective concentration, MEC) . Dosages necessary to achieve the MEC will depend on individual
- Dosage intervals can also be determined using the MEC value. Preparations should be administered using a regimen, which maintains brain levels above the MEC for 10-90% of the time, preferably between 30-90% of the time and most preferably between 50-90% of the time during the course of treatment.
- the number of administrations will vary depending upon the type and severity of the disease to be treated. In some embodiments, adminstration will be once a month at least until improvement of the condition is achieved. In other embodiments, adminstration will be once every two months, once every three months, once every four months, once every six months or once per year.
- dosing can be of a single or a plurality of administrations, with the course of treatment lasting from several days to several weeks or until diminution of the disease state is achieved.
- compositions to be administered will, of course, be dependent on the subject being treated, the severity of the affliction, the judgment of the prescribing physician, etc .
- a pack or dispenser device such as an FDA approved kit, which may contain one or more unit dosage forms containing the active ingredient.
- the pack or dispenser device may be accompanied by instructions for administration.
- the pack or dispenser may also be accommodated by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions or human or veterinary administration.
- Such notice for example, may be of labeling approved by the U.S. Food and Drug Administration for
- compositions comprising a preparation of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition, as if further detailed above.
- the present inventors predict that inhibition of the CXCR4 /CXCL12 signaling by AMD3100 may affect the toxic cascade of glutamate release from astrocytes and the eventual neuronal apoptosis in ALS .
- experiments were conducted to evaluate the intrinsic CXCR4 receptor levels of a transgenic mice model of ALS and to investigate the changes in CXCR4 levels during disease progression by administering AMD3100, which is known as antagonist for CXCR4 receptor, in order to examine its effect on ALS pathology.
- the transgenic mouse model of ALS expresses high copy number of mutant super oxide dismutase 1 (SOD1) which is a gene that is responsible for up to twenty percent of familial cases of ALS.
- SOD1 super oxide dismutase 1
- B6SJL-Tg (S0D1 G93A ) IGur-J mice are the most aggressive murine model of ALS but in many aspects this model mimics clinical symptoms and pathological processes that occur in ALS patients.
- Spinal cord homogenates of diseased G93A and their non- transgenic litter mates (LM) mice collected throughout disease progression at presymptomatic, symptomatic and final stage were subjected to Western blot analysis in order to determine the CXCR4 levels.
- LM non- transgenic litter mates
- CXCR4 stromal-derived factor la
- the present inventors treated G93A female mice subcutaneously with either AMD3100 or PBS, starting at 70 days old. Six mice received AMD3100 once a week, eight mice received AMD3100 twice a week, and seven mice received PBS once a week .
- Figure 3A shows mice that were treated with AMD3100 once and twice a week died at ⁇ 170 days old, which is about 14 days more than control mice. The weight loss of these mice was also smaller than the weight loss of PBS mice (Fig. 3B) . However, performance in the Rotarod test, which resembles motor function, was better among mice that received AMD3100 twice a week, whereas mice that received AMD3100 once a week performed similarly to the control group.
- AMD3100 treatment for once and twice a week thus extended the survival in about 14 days, compared with mice treated with PBS (Figs. 4A-4C) .
- the treatment resulted in less weight loss as disease retrogrades (Fig. 5A) .
- the improvement in motor function, detected by Rotarod test, was remarkable throughout disease progression mostly among mice treated twice a week with AMD3100, whereas mice treated only once a week showed improvement only at 50% of running ability or less.
- microglial-neuronal interactions that lead to MN degeneration remains elusive.
- the present inventors measured reduction of markers specific for activated microglia related to their contribution of the neurodegenerative network in ALS pathology, in the transgenic SOD1-G93A rodents, the most widely used model for the disease. All markers tested, including Iba-1 and cd36 resulted in significant reduction in its levels (Fig. 7A-7B) .
- B-CNS-B blood-Central Nervous System barrier
- BBB blood brain barrier
- BSCB blood-spinal cord barrier
- BCSFB blood-cerebrospinal fluid barrier
- TJPs tight junction proteins
- ZO-1 The loss of tight junction proteins (TJPs) occludin and ZO-1 in the microvasculature has been also shown to be mediated by various cytokines such as monocyte chemoattractant protein-1 (MCP1), TNF-a, IL- ⁇ , and IFN- ⁇ .
- MCP1 monocyte chemoattractant protein-1
- TNF-a TNF-a
- IL- ⁇ interleukin-1
- IFN- ⁇ interleukin-1
- microhemorrhage with release of neurotoxic hemoglobin-derived products reductions in microcirculation and hypoperfusion.
- Endothelial cells play an important role in B-CNS-B function.
- B-CNS-B dysfunction is recognized to participate in neurodegenerative disorders. Cerebral vascular endothelial cells develop highly selective barrier which controls the exchanges between blood and brain or blood and spinal cord compartments for the maintenance and regulation of the neuronal microenvironment.
- TJPs such as ZO-1, occludin and the claudin family exist in cerebral vascular endothelial cells, which are the most crucial factors modulating barrier integrity. It has been suggested that B-CNS-B dysfunction in ALS and Alzheimer's disease (AD) are likely related to the injury or dysregulation of TJPs. The expression of TJPs has been reported to contribute to barrier function.
- ZO-1 and claudin-5 are the most important components for cell barrier integrity. Claudin-5 can greatly reduce dextran permeability and improve transendothelial electrical resistance and plays an essential role in the earliest stage of CNS
- ZO-1 serves as a bridge between transmembrane proteins and skeleton proteins, and this interaction is important to the stability and function of endothelial barrier.
- Occludin has also been suggested to play a key role in the barrier function of the TJPs. All these three proteins are known to be reduced by 40%- 60% in both animal models of ALS and humans, even prior to disease onset (Zhong et al . , 2008) . Therefore, the present inventors focused on these TJPs in an experimental study, and found that chronic administration of AMD3100 was effective in restoring the expression of these TJPs (Figs. 9A-9C) . This data reveal a novel pharmacological effect of AMD3100 on endothelial barrier, which improves the barriers and thus prevents additional damage .
- Oligodendrocytes in CNS, and Schwann cells in the peripheral nervous system (PNS) are responsible for the myelin sheaths surrounding neurons which provide electrical insulation essential for rapid signal conduction.
- Schwann cells also participate in the clearance of debris and in guiding the axon after neuron damage
- Schwann cells are in intimate contact with the full length of the axons of lower motor neurons.
- Schwann cells also participate—in concert with peripheral macrophages—in clearing debris and in guiding the recovering axon (Ilieva et al . , 2009) .
- Oligodendrocyte dysfunction was also prevalent in human ALS, as gray matter demyelination and reactive changes in oligodendrocyte progenitors (NG2+ cells) were observed in motor cortex and spinal cord of ALS patients.
- NG2+ cells oligodendrocyte progenitors
- Selective removal of mutant SOD1 from oligodendroglia substantially delayed disease onset and prolonged survival in ALS mice, suggesting that ALS-linked genes enhance the vulnerability of motor neurons and accelerate disease by directly impairing the function of oligodendrocytes (Kang et al . , 2013) .
- neurotransmitter that triggers motor neurons to fire, can elicit a cascade of toxic events in the postsynaptic motor neuron including repetitive activation of glutamate receptors and the corresponding increase in calcium influx, thus overriding the storage abilities of mitochondria and endoplasmic reticulum (ER) .
- Contributing to this phenomenon is a failure to rapidly clear extracellular glutamate through deficiency in the glutamate transporter EAAT2 in the astrocytic processes that surround synapses of motor neurons and is responsible for about 95% of total glutamate transport at the synapses (Le Verche et al . , 2010) .
- ALS amyotrophic lateral sclerosis
- Kang SH Li Y, Fukaya M, Lorenzini I, Cleveland DW, Ostrow
- lateral sclerosis role and therapeutic potential of astrocytes.
Abstract
Description
Claims
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US201361871954P | 2013-08-30 | 2013-08-30 | |
PCT/US2014/053352 WO2015031722A1 (en) | 2013-08-30 | 2014-08-29 | Method for treating amyotrophic lateral sclerosis by inhibition of cxcr4/cxcl12 signaling |
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US20210023264A1 (en) * | 2019-07-08 | 2021-01-28 | The Board Of Regents Of The University Of Texas System | Use of immune modulators to improve nerve regeneration |
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GB9126677D0 (en) | 1991-12-16 | 1992-02-12 | Johnson Matthey Plc | Improvements in chemical compounds |
EP1061944B1 (en) | 1998-03-13 | 2004-01-28 | The University Of British Columbia | Therapeutic chemokine receptor antagonists |
CA2305787A1 (en) | 2000-05-09 | 2001-11-09 | The University Of British Columbia | Cxcr4 antagonist treatment of hematopoietic cells |
EP1571146A4 (en) | 2002-12-10 | 2010-09-01 | Ono Pharmaceutical Co | Nitrogen-containing heterocyclic compounds and medicinal use thereof |
CA2509711A1 (en) * | 2002-12-13 | 2004-07-01 | Smithkline Beecham Corporation | Piperidine derivatives as ccr5 antagonists |
EP1724263B1 (en) | 2004-03-10 | 2014-03-05 | Kureha Corporation | Basic amine compound and use thereof |
US8168783B2 (en) | 2005-11-18 | 2012-05-01 | Ono Pharmaceutical Co., Ltd. | Chemokine receptor antagonists and use thereof |
BRPI0707446A2 (en) | 2006-02-02 | 2011-05-03 | Allergan Inc | compositions and methods for the treatment of ophthalmic disease |
JPWO2010147094A1 (en) | 2009-06-16 | 2012-12-06 | 小野薬品工業株式会社 | Compound having spiro-bonded cyclic group and use thereof |
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2014
- 2014-08-29 EP EP14776926.9A patent/EP3038617A1/en not_active Withdrawn
- 2014-08-29 US US14/915,242 patent/US20160206592A1/en not_active Abandoned
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